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Preventives and remedies for diffuse lung diseases

a technology for diffuse lung disease and preventive and therapeutic agents, which is applied in the direction of fusion polypeptides, peptide/protein ingredients, unknown materials, etc., can solve the problems of suppressing such apoptosis, no preventive and therapeutic agent for diffuse lung disease has been known, and the side effects of steroids are well known

Inactive Publication Date: 2005-06-14
MOCHIDA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a preventive and therapeutic agent for diffuse lung diseases that acts by suppressing apoptosis. The agent contains an apoptosis-suppressing substance, such as a Fas antagonist or an anti-Fas ligand antibody, as its effective component. The invention is based on the finding that pathology is improved in a model of diffuse lung diseases by the apoptosis-suppressing substance. The preventive and therapeutic agent can be used for various diffuse lung diseases, such as cryptogenic interstitial lung diseases, drug-induced diffuse lung diseases, and infectious diffuse lung diseases. The method involves administering the apoptosis-suppressing substance to prevent or treat diffuse lung diseases.

Problems solved by technology

The steroids, however, are well known for their side effects, and delicate care should be taken for the timing, dose and duration of the administration (Konnichi-no Chiryo-Shishin (Therapeutic Guide Today) 1997, Hinohara S. et al. ed
However, it has been still unknown whether the apoptosis mediated by the Eas and the Fas ligand is directly or indirectly involved in the pathology of the diffuse lung diseases, and no preventive and therapeutic agent for diffuse lung diseases has been known which acts by suppressing such apoptosis.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Toxicity Study of shFas(nd29)-Fc

(1) Test Method

[0083]Male, 6 week BDF1 mice (manufactured by Charles River Japan) were administered with shFas(nd29)-Fc at a dose of 10 and 30 mg / kg once in every 2 days for 12 days, namely, for 7 times in total from their tail vein to evaluate the effect of the reagent. The experiment was conducted by dividing the mice into 3 groups each consisting of 3 animals, namely, into the control group, the group administered with 10 mg / kg of the shFas(nd29)-Fc, and the group administered with 30 mg / kg of the shFas(nd29)-Fc. In order to administer an equal amount protein, namely, 30 mg / kg of the protein to each group, the control group was administered with 30 mg / kg of human serum albumin; the group administered with 10 mg / kg of the shFas(nd29)-Fc was administered with 10 mg / kg of the shFas(nd29)-Fc and 20 mg / kg of the human serum albumin; and the group administered with 30 mg / kg of the shFas(nd29)-Fc was administered with 30 mg / kg of the shFas(nd29)-Fc.

[0084]...

example 2

Effects of shFas(nd29)-Fc in Ameliorating the Bleomycin-Induced Pulmonary Fibrosis Model Mouse

(1) Preparation of Bleomycin-Induced Pulmonary Fibrosis Model

[0086]Male, 6 week ICR mice (manufactured by Kyudo K. K.) were used in the experiment. The mice were weighed, intraperitoneally administered with pentobarbital (manufactured by Dinabot Co.) for anesthetization. The mice were then administered with 50 μl solution of bleomycin chloride (manufactured by Nippon Kayaku) dissolved in physiological saline to 4 mg / kg.

(2) Administration of shFas(nd29)-Fc

[0087]The mice were administered with shFas(nd29)-Fc by the procedure as described below. Intravenous administration was conducted at day 7 and day 10 after the bleomycin administration at a dose of 50 μg / mouse. Administration of shFas(nd29)-Fc by inhalation to lung was conducted at day 2, 4, 6, and 8 after the bleomycin administration, or at day 2, 4, 6, 8, 10, and 12 after the bleomycin administration by setting 10 ml of 50 μg / ml shFas(nd...

example 3

Production of Anti-Mouse Fas Ligand Antibody and its Purification

(1) Production of Anti-Mouse Fas Ligand Antibody

[0101]A plasmid containing human elongation factor (EF) promoter, and in its downstream, the gene coding for the chimeric protein prepared by fusing the extracellular domain of mouse Fas ligand from mouse Fas ligand WX2 (J. Immunology, vol. 157, pages 3918-3924, 1996) and the cytoplasmic domain, the transmembrane domain, and a part of the extracellular domain (from N terminal to 78th amino acid) of mouse CD40 ligand was prepared by genetic engineering means (Mizushima-Nagata, Nucleic Acids Research, vol. 18, page 5322, 1990). The plasmid was transfected in WR19L cell to obtain a recombinant cell W40LFL expressing the mouse Fas ligand on its cell membrane for use as the antigen to be administered. Armenian hamsters were used for the animals to be immunized. The Armenian hamsters were subcutaneously administered with 1×107 W40LFL mixed with Freund complete adjuvant, and a m...

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Abstract

Preventives and remedies for diffuse lung diseases whereby apoptosis can be inhibited and thus favorable preventive / therapeutic effects can be established.These drugs contain apoptosis-inhibiting substances as the active ingredient.The above apoptosis-inhibiting substances include Fas antagonists and Fas / Fas ligand binding inhibitors such as Fas derivatives and anti-Fas ligand antibodies.

Description

[0001]This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT / JP98 / 05025 which has an International filing date of Nov. 9, 1998, which designated the United States of America.TECHNICAL FIELD[0002]This invention relates to preventives and remedies for diffuse lung diseases which contain an apoptosis-suppressing substance as their effective component.BACKGROUND ART[0003]Fas is a cell surface protein which transmits apoptosis signal to the cell, and Fas is recognized by Fas antibody (Yonehara, S. et al., J. Exp. Med., vol. 169, 1747-1756, 1989) which is a monoclonal antibody produced by immunizing a mouse with human fibroblast. Fas gene was recently cloned by Itoh, N. et al., and it was then found out that Fas is a cell membrane protein of about 45 kD, and from the amino acid sequence, it was revealed that Fas is a member of TNF receptor family (Cell, vol. 66, pages 233-243, 1991). Mouse Fas gene was also cloned (Watanabe-Fukunaga, R. et al...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07K14/705C07K14/435C07K16/28C07K16/18A61K38/00A61P11/00C12P21/08
CPCC07K16/2875C07K14/70578A61K38/00A61K2039/505C07K2319/30C07K2319/00A61P11/00
Inventor KUWANO, KAZUYOSHI
Owner MOCHIDA PHARM CO LTD
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